Better adjuvants are needed for use with vaccines for pathogens that may be used as weapons of mass destruction or terror. For example, the currently used smallpox vaccine is a live virus vaccine that may not be used in immunocompromised individuals and may cause heart inflammation, inflammation of the membrane covering the heart, or a combination of these two problems in immunocompetent individuals. The development of better adjuvants may allow subunit immunogens (that may be safer than a live virus vaccine) to be used as a vaccine to protect against smallpox or other pox viruses. Another example where a better vaccine is needed is the currently used anthrax vaccine. The current anthrax vaccine is injected just under the skin in a series of 6 doses over 18 months, followed by a booster dose given each year. A better adjuvant and delivery system may allow the anthrax vaccine to induce protective immunity with fewer immunizations and less frequent booster immunizations. We have determined that a low molecular weight activator of mast cells (mast cell activator, MCA) exhibits significant adjuvant activity when coadministered with a subunit protein immunogen by the nasal route. We propose to further evaluate the adjuvant activity of MCA and monitor for adverse effects of this novel adjuvant when coadministered with anthrax protective antigen by various routes. We will also evaluate its ability to induce protective immunity in mice against a lethal challenge with anthrax lethal toxin. Our long term goal is to develop safe and effective adjuvants for use with antigens that induce protective immunity against select agent pathogens or their toxic products. Accordingly, our specific aims are: Specific Aim 1: Evaluate the adjuvant activity of MCA when coadministered with anthrax protective antigen by the nasal, gastric, intradermal or subcutaneous routes. Specific Aim 2: Determine if immunization with MCA and protective antigen protein induces protection against a lethal challenge with anthrax lethal toxin.